Friday, 30 April 2010

A study reported in today’s BMJ confirms that multiple sclerosis is probably an epigenetic disease with in utero exposure to low vitamin D levels determining disease susceptibility in later life. Judith Staples and colleagues show that low maternal exposure to ultraviolet radiation in the first trimester of pregnancy is independently associated with subsequent risk of MS in their offspring in Australia. The adjusted incidence rate ratio for MS is 1.32 (95% confidence interval 1.10 to 1.58, P<0.01) for those subjects born in November or December compared with those born in May or June. As expected the inverse is observed in the Northern hemisphere. How exposure to low vitamin D levels in utero determines disease susceptibility is unknown but is clearly an area of major scientific interest and is being actively pursued by our group. The public health implications of these observations are profound and support the need for high-dose vitamin D supplementation in early pregnancy. In a collaborative study between Queen Mary University of London and Oxford University we are exploring this phenomenon further and would urge anyone with MS to complete our online survey.
click here to complete online survey.

Classification of MS patients as sero-negative or sero-positive with respect to previous JC virus exposure is possible with a new assay. Thirteen out of 13 patients who developed PML all had evidence of prior infection with JCV, as measured by the presence of anti-JCV antibodies. This assay will help stratify patients into high and low risk groups and modify the risk for individual subjects; those with positive antibodies will have double the risk of getting PML (this is based on the observation that ~54% of subjects in the original natalizumab trial were sero-positive. The corollary to this is that subjects seronegative have a very low risk of getting the disease.

After stopping natalizumab treatment CSF lymphocytes counts may recover within 3 months. This implies that immune surveillance is restored shortly after cessation of natalizumab therapy and coincides with observation that IRIS in the setting of natalizumab-associated PML also occurs at this time-point unless hastened by plasma exchange.

Cross-sectional and longitudinal testing in a large cohort of MS patients demonstrates that there is no substantial change in the presence of JCV DNA in the plasma, whole blood or urine with natalizumab treatment. Less than 1% (4 out of 1397) patients had JCV DNA in their blood, which did not predict the occurrence of PML. In addition, in cases that developed PML plasma samples were negative prior to diagnosis. This study and other recent studies seriously calls into question the validity of the results of other smaller studies suggesting that natalizumab increases peripheral blood and urine JCV detection rates. From a practical perspective we cannot use plasma, peripheral blood or urine JCV DNA detection to predict PML risk in natalizumab-treated patients. Will this study end the debate? Please watch this space.

[P05.036] Long-Term Follow-Up of Immune Thrombocytopenia after Treatment of Multiple Sclerosis Patients with Alemtuzumab in CAMMS223
Edward Fox, Round Rock, TX, N. A. on Behalf of the CAMMS223 Study Group

Cutaneous symptoms of ITP went unrecognized in the 1st case until onset of a fatal cerebral haemorrhage. Five other cases were subsequently diagnosed with ITP with onset between 1.5 and 16 months after alemtuzumab. In one case ITP resolved without treatment. In 2 cases, remission was achieved with corticosteroid treatment alone and in the other 2 patients following treatment with rituximab cycle. On balance these results suggest that ITP is a manageable side effect of alemtuzumab provided it is detected and treated early.

At year 4: (1) 77% of alemtuzumab-treated patients were relapse–free compared to 49% of IFNB-1a-treated patients; (2) 91% of alemtuzumab-treated patients were disease progression free vs. 68% of IFNB-1a patients (p<0.001); (3) 71% of alemtuzumab patients were clinically disease-free v. 35% for IFNB-1a at year 4 (p<0.001). A treatment effect at year 4 in patients who only completed 2 annual cycles of alemtuzumab during the first 12 months supports the strategy of aggressive induction therapy in early MS. No wonder PwMS want this drug.

Wednesday, 14 April 2010

Of all the viruses EBV is the clear leader of the pack as being the most likely cause of MS. Could a specific strain of EBV cause MS? A superficial look at has not revealed obvious difference between EBV strains in people with MS and control subjects.

Sunday, 11 April 2010

Causation theory is a complex science and involves philosophy and the social sciences. Causation is rarely, if ever, a black-or-white issue. The first to appreciate this was Robert Koch who discovered the cause of TB; in fact he had to formulate his postulates to convince his peer-group that he had found the cause of TB. Even then it took Robert Koch more than a decade to convince the scientific community of the significance of his findings.

The issue of causation theory has come up recently in relation to our posts on CCSVI. If you are interested in reading more about causation and causation theory, specifically in relation to MS, I would recommend the following articles as a starter:

Using a very cool technology called optical coherence tomography (OCT) a new study has demonstrated progressive thinning of the retinal nerve fibre layer as a function of time in some patients with MS. Importantly, this thinning occurred in either the presence or absence of previous optic neuritis (focal inflammation in the optic nerve) and was associated with clinically significant visual loss.

These findings indicate that asymptomatic or sub-clinical nerve fibre (or axonal loss) occurs in the visual pathways in MS.

Opinion:

1. If these findings can be confirmed it will add credence to the claims that MS is a primary neurodegenerative disease. "I hope not."

2. This study supports the use of OCT as a method to evaluate the effectiveness of neuroprotective agents in MS; we will need to show that drugs or combinations of drugs stop or at least slow down this loss of nerve fibres to accept that they are "neuroprotective".

PML Risk Infographic

Holistic Management of MS ver. 7.0

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